Knockout Corner: Neurobehavioural consequences of a serotonin 5-HT2C receptor gene mutation

Studies employing nonselective serotonin 5-HT2C receptor agonists and antagonists have implicated this receptor subtype in many of the actions of serotonin. To further examine the function of this receptor, 5-HT2C receptor mutant mice were generated; studies of these animals reveal pleiotropic neurobehavioural effects of the mutation. Three examples are described: (1) Mutants exhibit chronically elevated food intake and the development of an obesity syndrome during the ‘middle-age’ portion of their lifespan. Their potential utility as a model of human obesity is further indicated by their enhanced sensitivity to high-fat feeding, leading to the development of type 2 diabetes. (2) 5-HT2C receptor mutants also display infrequent and sporadic spontaneous seizures. Further studies suggested the presence of globally enhanced neuronal network excitability in these mice. These findings raise the possibility that 5-HT2C receptors mediate a role for serotonin in the suppression of seizure activity. (3) Behavioural analysis of mutant mice revealed abnormal performance in a spatial learning task and altered exploratory behaviour, associated with perturbed long-term potentiation restricted to the dentate gyrus perforant path synapse. Taken together, the above findings implicate 5-HT2C receptors in the serotonergic regulation of feeding, neuronal network excitability, and hippocampal function.